Molecular Basis of Action of the Putative Oncogene BCL-6

描述（由申请人提供）：原癌基因BCL 6编码一种POZ/BTB-锌指转录抑制因子，其对正常淋巴细胞发育至关重要。当BCL 6异常表达时，其导致弥漫性大B细胞淋巴瘤（DLBCL）的发展。在上一次资助期间，我们发现了一种新的辅阻遏物BCOR，它与BCL 6一起发挥作用。在此资助期间，我们已经证明BCOR与几种polycomb group（PcG）蛋白形成复合物，包括NSPC 1（BMI 1同源物），泛素-H2 A E3连接酶，RNF 2和其他可能能够进一步修饰染色质的蛋白质。我们发现BCOR存在于多个BCL 6靶基因上，其抑制可能有助于淋巴瘤的发生。因此，BCOR复合物的蛋白质提供了治疗B细胞淋巴瘤的候选治疗靶标。我们还发现BCOR是逆转录病毒诱导的B细胞淋巴瘤中常见的插入位点，这些整合导致BCOR mRNA表达升高。这强烈表明BCOR作为致癌基因发挥作用。BCOR还在人类发展方面发挥着更广泛的作用。人类BCOR的突变导致男性致死性X连锁眼面心齿（OFCD）综合征，我们发现BCOR的亚型小鼠突变部分模拟OFCD表型。最后，BCOR和NSPC 1的不适当水平可以破坏ES细胞分化，这与BCOR复合物在干细胞维持或分化中的作用一致。我的中心假设是，BCOR介导的抑制，通过表观遗传机制，是重要的淋巴瘤。这项建议的目的是：第一，以确定的作用，BCOR在B细胞淋巴瘤发生在细胞培养和在体内，第二，解剖的分子和表观遗传机制的BCOR阻遏复合物。这里提出的工作在几个方面是重要的。首先，BCL 6参与临床上重要的B细胞淋巴瘤，BCOR复合物是介导BCL 6致癌活性的强有力候选物。其次，我们的初步数据表明BCOR也可以作为一个致癌基因。第三，这些研究将有助于阐明BCOR表观遗传抑制机制，这与许多生物学过程有关，包括眼睛，颅面和心脏发育以及造血和淋巴瘤发生。第四，我们的研究将有助于确定DLBCL的潜在治疗靶点。公共卫生相关性：这项工作与公共卫生有明显的相关性。BCL 6是一种重要的癌蛋白，参与了高达50%的DLBCL，一种常见的非霍奇金淋巴瘤亚型，我们的数据表明BCOR与BCL 6一起发挥功能。我们的初步数据表明，BCOR也作为一种癌蛋白。已经有一种潜在的治疗方法部分基于这项资助的工作，即将进行临床试验，这里提出的工作应该允许设计未来改进的抗淋巴瘤治疗。

DESCRIPTION (provided by applicant): The proto-oncogene BCL6 encodes a POZ/BTB-zinc finger transcriptional repressor that is essential for normal lymphocyte development. When BCL6 is aberrantly expressed it leads to the development of diffuse large B cell lymphomas (DLBCL). During the last grant period we identified a novel corepressor, BCOR, which functions with BCL6. In this funding period we have shown that BCOR forms a complex with several polycomb group (PcG) proteins, including NSPC1 (a BMI1 homolog), the ubiquitin-H2A E3 ligase, RNF2, and other proteins potentially capable of further epigenetic modification of chromatin. We found that BCOR is present at multiple BCL6 target genes whose repression is likely to contribute to lymphomagenesis. Thus proteins of the BCOR complex provide candidate therapeutic targets for treatment of B cell lymphoma. We also have found that BCOR is a common insertion site in retrovirally-induced B cell lymphomas, and that these integrations cause elevated BCOR mRNA expression. This strongly suggests that BCOR acts as an oncogene. BCOR also plays a more widespread role in human development. Mutations in human BCOR cause the male-lethal X- linked Oculofaciocardiodental (OFCD) syndrome, and we showed that a hypomorphic mouse mutation in Bcor partially mimics the OFCD phenotype. Finally, inappropriate levels of BCOR and NSPC1 can disrupt ES cell differentiation, consistent with a role for the BCOR complex in stem cell maintenance or differentiation. My central hypothesis is that BCOR-mediated repression, via epigenetic mechanisms, is important for lymphomagenesis. The aims of this proposal are: first, to determine the role of BCOR in B cell lymphomagenesis both in cell culture and in vivo and second, to dissect the molecular and epigenetic mechanisms of the BCOR repression complex. The work proposed here is significant in several respects. First, BCL6 is involved in clinically important B cell lymphomas and the BCOR complex is a strong candidate to mediate BCL6 oncogenic activity. Second, our preliminary data suggest BCOR also can act as an oncogene. Third, these studies will help elucidate BCOR epigenetic repression mechanisms, which are relevant to many biological processes including eye, craniofacial, and heart development as well as hematopoiesis and lymphomagenesis. Fourth, our studies will help identify potential therapeutic targets for DLBCL. PUBLIC HEALTH RELEVANCE: The work has clear relevance to public health. BCL6 is and important oncoprotein involved in up to 50% of DLBCL, a common subtype of non-Hodgkin's lymphoma, and our data indicate that BCOR functions with BCL6. Our preliminary data suggest that BCOR also acts as an oncoprotein. Already a potential therapy based in part on work funded by this grant is nearing clinical trials, and the work proposed here should permit the design of future improved anti-lymphoma therapy.